MicroRNAs (miRNAs, miRs) are a class of highly conserved, non-coding small RNA molecules that mediate translation in a cell or organism by negatively regulating the expression of their target genes and thus causing translational arrest, mRNA cleavage or a combination thereof. See Bartel D P. Cell. (2009) 136(2):215-33. By targeting multiple transcripts, miRNAs regulate a wide range of biological processes, including apoptosis, differentiation and cell proliferation, thus aberrant microRNA function can lead to cancer (see Ambros V. Nature. (2004) 431(7006):350-5) and as such, miRNAs have recently been identified as biomarkers, oncogenes or tumor suppressors. See, e.g., Croce, C M, Nat Rev Genet. (2009) 10:704-714).
Colorectal cancer (CRC) is the third most common malignancy and the second most common cancer-related cause of death in the United States. See, Hegde S R, et al., Expert review of gastroenterology & hepatology. (2008) 2(1):135-49). There are many chemotherapeutic agents used to treat cancer; however pyrimidine antagonists, such as fluoropyrimidine-based chemotherapeutic agents (e.g., 5-fluorouracil, S-1) are the gold standard for treating colorectal cancer. Pyrimidine antagonists, block the synthesis of pyrimidine containing nucleotides (Cytosine and Thymine in DNA; Cytosine and Uracil in RNA). Because pyrimidine antagonists have similar structures when compared to endogenous nucleotides, they compete with the natural pyrimidines to inhibit crucial enzymatic activity involved in the replication process leading to the prevention of DNA and/or RNA synthesis and inhibition of cell division.
5-fluoro-1H-pyrimidine-2,4-dione (5-Fluorouracil, 5-FU) is a well known pyrimidine antagonists and is the focus of many adjuvant chemotherapeutic strategies, such as Carac® cream, Efudex®, Fluoroplex®, and Adrucil®. It is well established that 5-FU targets a critical enzyme, thymidylate synthase (TYMS or TS), which catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) an essential step in DNA biosynthesis. See, Danenberg P V. Biochimica et biophysica acta. (1977) 473(2):73-92. However, despite the steady improvement of 5-FU-based therapy, the patient response rate to 5-FU-based chemotherapy remains modest, due to the development of drug resistance. See, Longley D B, et al., Apoptosis, Cell Signaling, and Human Diseases. (2007) p. 263-78.
One major mechanism utilized by tumor cells is to circumvent the apoptotic pathways by developing resistance to common therapeutic agents such as 5-FU. See, Gottesman M M, et al. Nature Rev. Cancer. (2002) 2(1):48-58). Thus, it is essential to better understand the mechanisms of drug resistance and to discover novel strategies to further improve the effectiveness of 5-FU.